title: Synthetic trimethyllysine receptors that bind histone 3, trimethyllysine 27 (H3K27me3) and disrupt its interaction with the epigenetic reader protein CBX7.
abstract: Post-translational modifications act as 'on' or 'off' switches causing downstream changes in gene transcription. Modifications such as trimethylation of lysine 27 on histone H3 (H3K27me3) cause repression of transcription and stable gene silencing, and its presence is associated with aggressive cancers of many types. We report here macrocyclic host-type compounds that can bind H3K27me3 preferentially over unmethylated H3K27, and characterize their binding affinities and selectivities using a convenient dye-displacement method. We also show that they can disrupt the protein-protein interaction of H3K27me3 with the chromobox homolog 7 (CBX7), a methyllysine reader protein, using fluorescence polarization. These results show that sub-micromolar potencies are achievable with this family of host compounds, and suggest the possibility of their use as new tools to induce the disruption of methyllysine-mediated protein-protein interactions and to report on lysine methylation in vitro.
authors.affiliation: Department of Chemistry, University of Victoria, Victoria, BC V8W 3V6, Canada.
authors.forename: Sara
authors.initials: S
authors.lastname: Tabet
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Douglas
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Daze
authors.forename: Graham A E
authors.initials: GA
authors.lastname: Garnett
authors.forename: Kevin J H
authors.initials: KJ
authors.lastname: Allen
authors.forename: Emma M M
authors.initials: EM
authors.lastname: Abrioux
authors.forename: Taylor T H
authors.initials: TT
authors.lastname: Quon
authors.forename: Jeremy E
authors.initials: JE
authors.lastname: Wulff
authors.forename: Fraser
authors.initials: F
authors.lastname: Hof
mesh_terms: D047250:Calixarenes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D005454:Fluorescence Polarization; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008745:Methylation; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D063150:Polycomb Repressive Complex 1 / Q000737:chemistry / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D062165:Receptors, Artificial / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
chemical_list: C503627:CBX7 protein, human; D006657:Histones; D010636:Phenols; D062165:Receptors, Artificial; C121325:calix(4)arene; D047250:Calixarenes; D063150:Polycomb Repressive Complex 1
keywords: CBX7; Calixarenes; Epigenetics; H3K27; H3K27me3; Methylation; Post-translational modifications; Protein–protein interactions; Supramolecular chemistry; chromobox homolog 7; histone H3 lysine 27; histone H3 lysine 27 trimethylated